Strong evidence from family and twin studies demonstrates that major depressive disorder (MDD) is heritable, yet there has been limited progress in identifying the actual genes involved. A separate, perhaps overlapping set of genes is expected to play a role in individual variation in treatment response in MDD. We propose to characterize genetically, using a large set of markers in many genes, patients who differ in their response to standard treatments as defined in the STAR*D protocol. We will focus initially on two sets of genes most likely to play a role in the etiology of major depression: 1) genes selected on neurobiological grounds because of their known involvement in pathways thought to be important in mood disorders; and 2) genes implicated primarily by their positions within genomic regions implicated by genetic linkage or association studies of major mood disorders and related conditions. These two approaches are complimentary since the neurobiological candidates arise directly from existing etiologic hypotheses while the positional candidates may lead to the discovery of unexpected pathways. Our ultimate goal is study markers representing every common functional variation in the human genome, once such genome-wide studies become technologically feasible. We will utilize state-of-the-art, high-throughput genotyping methods as well as sophisticated methods of genetic analysis that take into account haplotypes and multi-locus interactions in addition to standard, single-marker analyses. Primary comparisons will be performed with the group of cases who respond to citalopram and those who do not, but analyses may be possible in other treatment groups as well, depending on sample size. The results may provide new insights into the genetic determinants of treatment response in MDD, and may also shed light on genes contributing to risk for MDD, with the promise of novel treatment approaches and improved targeting of existing therapies.